Biomedical subjects

Gerald P Linette

Publications and source records attributed to Gerald P Linette.

16 recordsLinked to original sources

PubMed2005

Immunization using autologous dendritic cells pulsed with the melanoma-associated antigen gp100-derived G280-9V peptide elicits CD8+ immunity.

PURPOSE: To determine the toxicity, maximal tolerated dose, and clinical and immunologic response to autologous dendritic cells pulsed with melanoma-associated antigen gp100-derived G280-9V peptide. PATIENTS AND METHODS: Twelve HLA-A*0201(+) patients with advanced melanoma were administered dendritic cells pulsed with G280-9V peptide. Cohorts of three patients were administered 5 x 10(6), 15 x 10(6), and 50 x 10(6) cells i.v. every 3 weeks for six doses according to a dose escalation scheme. Three additional patients were treated at the highest dose. No additional cytokines or therapies were coadministered. The immunogenicity of G280-9V-pulsed dendritic cells was measured by IFN-gamma ELISPOT assay, tetramer assay, and (51)Cr release assay comparing prevaccination to postvaccination blood samples. Response to treatment was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: CD8(+) immunity to the native G280 was observed in 8 (67%) patients as measured by ELISPOT and in 12 (100%) patients as measured by tetramer assay. Of the 9 patients tested, 9 (100%) had measurable high-avidity CTL activity as defined by lysis of allogeneic melanoma lines, which coexpress HLA-A*0201 and gp100. The median follow-up of the entire cohort is 43.8 months. Two (17%) partial responses were observed and 3 (25%) patients had stable disease. The median survival of the treated population was 37.6 months. At this time, three patients are alive, including one patient who continues to respond without additional treatment. CONCLUSION: The high rate of immunization as measured by three independent assays and the occurrence of clinical regression support continued investigation of G280-9V peptide as a candidate epitope in melanoma vaccine formulations.

Adult↗

PubMed2005

Gene expression profiles predict early relapse in ovarian cancer after platinum-paclitaxel chemotherapy.

PURPOSE: Women with advanced epithelial ovarian cancer are routinely treated with platinum-paclitaxel chemotherapy following cytoreductive surgery, yet only approximately 20% achieve long-term disease-free survival. We hypothesized that differences in gene expression before treatment could distinguish patients with short versus long time to recurrence after administration of platinum-paclitaxel combination chemotherapy. EXPERIMENTAL DESIGN: To test this hypothesis, gene expression profiling of 79 primary surgically resected tumors from women with advanced-stage, high-grade epithelial ovarian cancer was done using cDNA microarrays containing 30,721 genes. Supervised learning algorithms were applied in an effort to develop a binary classifier that could discriminate women at risk for early (< or =21 months) versus late (>21 months) relapse after initial chemotherapy. RESULTS: A 14-gene predictive model was developed using a set of training samples (n = 51) and subsequently tested using an independent set of test samples (n = 28). This model correctly predicted the outcome of 24 of the 28 test samples (86% accuracy) with 95% positive predictive value for early relapse. CONCLUSIONS: Predictive markers for early recurrence can be identified for platinum-paclitaxel combination chemotherapy in primary ovarian carcinoma. The proposed 14-gene model requires further validation.

Adult↗

PubMed2005

Biomarkers in melanoma: stage III and IV disease.

The prognosis associated with Stage III melanoma is variable (17-65% 5-year survival) and primarily influenced by the number of lymph nodes involved, the presence of ulceration in a primary lesion, and the tumor burden present in each lymph node. In patients with metastatic (Stage IV) melanoma, the prognosis remains dismal (6-18% 5-year survival) and is influenced primarily by the sites (and extent) of metastatic involvement. Serum lactate dehydrogenase is the only prognostic biomarker useful in metastatic melanoma and it has been incorporated into the 2002 American Joint Committee on Cancer tumor, node, metastasis staging system. In this review, the known prognostic factors in Stage III and IV melanoma are reviewed. Selected investigational therapies and associated biomarkers are also discussed.

Biomarkers↗

PubMed2004

Targeted therapy in breast cancer: the HER-2/neu gene and protein.

The HER-2/neu oncogene, a member of the epidermal growth factor receptor or erb gene family, encodes a transmembrane tyrosine kinase receptor that has been linked to prognosis and response to therapy with the anti-HER-2-humanized monoclonal antibody, trastuzumab (Herceptin, Genentech, South San Francisco, CA) in patients with advanced metastatic breast cancer. HER-2/neu status has also been tested for its ability to predict the response of breast cancer to other therapies including hormonal therapies, topoisomerase inhibitors, and anthracyclines. This review includes an analysis of 80 published studies encompassing more than 25,000 patients designed to consider the relative advantages and disadvantages of the various methods of measuring HER-2/neu in clinical breast cancer specimens. Southern blotting, PCR amplification detection, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is reviewed along with the current studies designed to test whether HER-2/neu status can predict the response to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review will also evaluate the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.

Antineoplastic Agents↗

PubMed2004

Pharmacogenomics.

The discovery of the human genome and subsequent expansion of proteomics research combined with emerging technologies such as functional imaging, biosensors and sophisticated computational biology are producing unprecedented changes in today's healthcare. The expanding knowledge of the molecular basis of cancer has shown that significant differences in gene expression patterns can guide therapy not only for neoplastic conditions, but also for a variety of diseases including inflammatory disorders, cardiovascular disease and neurodegenerative processes. As a result, the fields of pharmacogenetics and pharmacogenomics have emerged as potential new testing platforms for the individualized management of patients. An individual's response to a drug is the complex interaction of both genetic and non-genetic factors. Genetic variants in the drug target itself, disease pathway genes, or drug metabolizing enzymes may all be used as predictors of drug efficacy or toxicity. In oncology, the SNP technology has focused on detecting the predisposition for cancer, predicting of toxic responses to drugs and selecting the best individual and combinations of anti-cancer drugs. Pharmacogenomics involves the application of whole genome technologies (e.g., gene and protein expression data) for the prediction of the sensitivity or resistance of an individual's disease to a single or group of drugs. Genomic microarrays and transcriptional profiling have the ability to generate hundreds of thousands of data points requiring sophisticated and complex information systems necessary for accurate and useful data analysis. This technique has generated a wealth of new information in the fields of leukemia/lymphoma, and solid tumor classification and prediction of metastasis, drug and biomarker target discovery and pharmacogenomic drug efficacy testing.

Drug Resistance, Neoplasm↗

PubMed2004

Targeted therapies for cancer 2004.

The regulatory agency approvals in the United States and Europe of imatinib mesylate (Gleevec) for patients with bcr/abl-positive chronic myelogenous leukemia, cetuximab (Erbitux) for patients with epidermal growth factor receptor overexpressing metastatic colorectal cancer, the antiangiogenesis agent bevacizumab (Avastin), and the proteasome inhibitor bortezomib (Velcade)--and the considerable public interest in new anticancer drugs that take advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatment--are driving a new era of integrated diagnostics and therapeutics. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene for patients with non-small cell lung cancer treated with gefitinib (Iressa) has intensified this interest. In this review, the history of targeted anticancer therapies is highlighted, with focus on the development of molecular diagnostics for hematologic malignancies and the emergence of trastuzumab (Herceptin), an antibody-based targeted therapy for HER-2/neu overexpressing metastatic breast cancer: The potential of pharmacogenomic strategies and the use of high-density genomic microarrays to classify and select therapy for cancer are briefly considered. This review also considers the widely held view that, in the next 5 to 10 years, the clinical application of molecular diagnostics will further revolutionize the drug discovery and development process; customize the selection, dosing, route of administration of existing and new therapeutic agents; and truly personalize medical care for cancer patients.

Aminoglycosides↗

PubMed2004

Breast cancer biomarkers and molecular medicine: part II.

In this second part of the two-part review of breast cancer biomarkers and molecular medicine, the first section will consider additional breast cancer prognostic factors, including oncogenes, tumor suppressor genes, cell adhesion molecules, invasion-associated proteins and proteases, hormone receptor proteins, drug resistance proteins, apoptosis regulators, transcription factors, telomerase, DNA repair and methylation and transcriptional profiling using high-density genomic microarrays. The second section will consider the prediction of therapy response using the techniques of pharmacogenetics and pharmacogenomics.

Biomarkers, Tumor↗

PubMed2003

HER-2/neu testing in breast cancer.

The testing of newly diagnosed breast cancer specimens for HER-2/neu status has achieved "standard of practice" status for the management of breast cancer in the United States. The discussion as to the best method to determine HER-2/neu status in these samples continues, with the fluorescence in situ hybridization method gaining popularity owing to the recent evidence that it, in comparison with immunohistochemical analysis, might more accurately predict clinical responses to trastuzumab-based therapies. With trastuzumab achieving excellent results in the treatment of HER-2/neu-positive advanced disease and under extensive evaluation in major clinical trials for its potential efficacy when used at earlier clinical stages, the potential role(s) for HER-2/neu testing as a predictor of response to other therapies being resolved by large prospective clinical outcome studies, and the more convenient gene-based chromogenic in situ hybridization technique "waiting in the wings," the saga of HER-2/neu testing in breast cancer will continue to unfold over the next several years.

Antibodies, Monoclonal↗

PubMed2003

Malignant melanoma 2003: predisposition, diagnosis, prognosis, and staging.

The incidence and mortality of melanoma has seemed to level off for certain groups after a steady increase during the last 50 years. This trend is suspected to be secondary to education efforts aimed at prevention and better detection and removal of thin, biologically benign melanomas. Since no effective systemic therapies exist for metastatic melanoma, early detection and removal of thin melanomas offer the best chance of cure. For thicker melanomas, sentinel lymph node biopsy has improved the accuracy of staging and prognostic evaluation. However, approximately one third of patients diagnosed with metastatic melanomas present without previous regional lymph node metastases. As the genomic understanding of melanoma's pathogenesis grows, new methods likely will be developed to more accurately identify the people at risk for melanoma, those who have high-risk melanomas, and those who have disseminated disease. We review current and potential biomarkers useful for the screening for and prevention, diagnosis, staging, and prognosis of melanoma.

Cytodiagnosis↗

PubMed2003

DNA ploidy and cell cycle analysis in breast cancer.

During the past 10 years there has been considerable interest in the application of new technologies to identify human malignancy and predict disease outcome. Markers of cell proliferation and the technologies of flow cytometry and image analysis for the determination of DNA total content in human tumor cells have been studied in breast cancer for 20 years. In this review, the uses and limitations of these technologies for the determination of ploidy status are discussed. This review also considers the prognostic significance and potential clinical utility of ploidy measurements, S phase calculation, and individual cell cycle regulatory biomarker expression levels.

Breast Neoplasms↗

PubMed2003

Biomarkers in melanoma: predisposition, screening and diagnosis.

Melanoma's incidence and mortality for certain groups has appeared to level off after a steady increase over the last half century. This trend is suspected to be due to better detection and removal of thin, biological early melanomas. However, to date, no prospective evidence exists to clearly demonstrate the efficacy of prevention and early detection in decreasing melanoma mortlity. Nonetheless, many studies suggest that both self-assessment of risk factors or clinician examination can identify a proportion of patients at highest risk for melanoma who may benefit from behavior modification (primary prevention) and routine screening (secondary prevention). Compromising these goals is the fact that neither the clinical or histologic diagnosis of melanoma is 100% accurate. Clinical diagnosis of melanoma, based on evaluation of a skin lesion's color and shape, correlates best with the experience of the clinician. Ancillary technologies have been developed to improve clinical accuracy of suspicious skin lesions but a subset of melanomas exist that do not fall in the spectrum of the 'ABCDE' guidelines commonly used for melanoma identification. Similarly, at the histologic level (the 'gold standard' of diagnosis), overlap exists between benign and malignant melanocytic proliferations leading to both over and underdiagnosis of melanoma. A better understanding of melanoma's pathogenesis has identified disease-related biomarkers that may more reliably differentiate a melanocytic nevus from melanoma. In this paper, we review current and novel, potentially more accurate, biomarkers and supplementary technologies that can be used for the prevention, screening and diagnosis of melanoma.

Animals↗

PubMed2003

Biomarkers in melanoma: staging, prognosis and detection of early metastases.

Currently, melanoma remains a surgical disease since early detection and excision of thin melanomas offers the best chance of a cure. Despite intensive clinical investigation, no effective systemic therapies exist for metastatic melanoma. Sentinel lymph node biopsy has greatly aided the staging and prognostic evaluation of primary cutaneous melanoma, however, approximately a third of patients diagnosed with metastatic melanomas present without prior regional lymph node involvement. Additional prognostic biomarkers exist which help determine the risk of advanced melanoma but the accuracy for each current marker is less than 100%. A greater understanding of the biology of melanomas and the development of new methods to identify patients with early (subclinical) metastatic disease may allow for selective and more effective therapy for patients at-risk for advanced disease. In this paper, current and novel potentially more accurate biomarkers for the staging and prognostic evaluation of melanoma patients, and for the detection of subclinical metastases are reviewed.

Biomarkers, Tumor↗

PubMed2003

Breast cancer biomarkers and molecular medicine.

The first part of this two-part review of established and emerging breast cancer biomarkers and molecular diagnostics considers breast cancer predisposition, screening tests for diagnosis, diagnosis using small specimens and metastatic lesions, micrometastatic disease and breast cancer prognosis assessment. Prognostic factors covered in this review include: cytogenetic markers, DNA ploidy and S phase determination, cell proliferation markers, cell cycle regulators and growth factor measurements including epithelial growth factor receptor, HER-2/neu and a variety of other relevant molecules controlling proliferation, differentiation and angiogenesis. The first section of part two will continue the consideration of breast cancer prognostic factors including oncogenes, tumor suppressor genes, cell adhesion molecules, invasion-associated proteins and proteases, hormone receptor proteins, drug resistance proteins, apoptosis regulators, transcription factors, telomerase, DNA repair and methylation and transcriptional profiling using high-density genomic microarrays. The second section of part two will consider the prediction of therapy response using the techniques of pharmacogenetics and pharmacogenomics.

Antibodies, Monoclonal↗

PubMed2003

The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy.

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. In this review, the association of HER-2/neu gene and protein abnormalities with prognosis and response to therapy with trastuzumab and to other therapies in breast cancer is presented. By considering a series of 80 published studies encompassing more than 25,000 patients, the relative advantages and disadvantages of Southern blotting, polymerase chain reaction amplification, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is presented as well as its potential impact on responses to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review also evaluates the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.

Adult↗

PubMed2002

Antimelanoma activity of CTL generated from peripheral blood mononuclear cells after stimulation with autologous dendritic cells pulsed with melanoma gp100 peptide G209-2M is correlated to TCR avidity.

Anchor residue-modified peptides derived from tumor-associated Ag have demonstrated success in engendering immune responses in clinical studies. However, tumor regression does not always correlate with immune responses. One hypothesis to explain this is that CTL resulting from such immunization approaches are variable in antitumor potency. In the present study, we evaluated this hypothesis by characterizing the activity of tumor-associated Ag-specific CTL. We chose an anchor residue-modified peptide from gp100, G209-2M, and used peptide-pulsed dendritic cells to generate CTL from PBMC of HLA-A2(+) normal donors. The specificities and avidities of the resulting CTL were evaluated. The results demonstrate that CTL generated by G209-2M can be classified into three categories: G209-2M-specific CTL which are cytotoxic only to G209-2M-pulsed targets; peptide-specific CTL which recognize both G209 and G209-2M peptides but not melanomas; and melanoma-reactive CTL which recognize peptide-pulsed targets as well as HLA-A2(+)gp100(+) melanomas. CTL that kill only peptide-pulsed targets require a higher peptide concentration to mediate target lysis, whereas CTL that lyse melanomas need a lower peptide concentration. Increasing peptide density on melanomas by loading exogenous G209 peptide enhances their sensitivity to peptide-specific CTL. High avidity CTL clones also demonstrate potent antimelanoma activity in melanoma model in nude mice. Injection of G209 peptide around transplanted tumors significantly enhances the antitumor activity of low avidity CTL. These results suggest that peptide stimulation causes expansion of T cell populations with a range of avidities. Successful immunotherapy may require selective expansion of the higher-avidity CTL and intratumor injection of the peptide may enhance the effect of peptide vaccines.

Animals↗

PubMed2002

Hypopigmentation associated with an adenovirus-mediated gp100/MART-1-transduced dendritic cell vaccine for metastatic melanoma.

BACKGROUND: Reports of vitiligo associated with metastases and rare cases of spontaneous regression of disease have fueled enthusiasm for immunologic approaches to the treatment of advanced melanoma. More recent strategies have focused on using antigen-presenting dendritic cells as vaccines. OBSERVATIONS: We observed 3 cases of leukoderma associated with a novel adenovirus-mediated gp100/MART-1-transduced dendritic cell (MART indicates melanoma antigen recognized by T cells). All 3 patients had advanced metastatic melanoma. Despite the development of this leukodermic response, all patients experienced disease progression while under treatment. CONCLUSION: We provide the initial evidence for effective induction of a leukodermic response with a gp100/MART-1-transduced dendritic cell vaccine.

Adenoviridae↗